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ScienceDirect SMC complexes link gene expression and genome architecture Jill M Dowen1 and Richard A Young1,2 The structural maintenance of chromosomes (SMC) complexes are associated with transcriptional enhancers, promoters and insulators, where they contribute to the control of gene expression and genome structure. We review here recent insights into the interlinked roles of SMC complexes in gene expression and genome architecture. Among these, we note evidence that SMC complexes play important roles in the regulation of genes that control cell identity. We conclude by reviewing diseases associated with SMC mutations. Addresses 1 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, United States 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States Corresponding author: Young, Richard A ([email protected])

Current Opinion in Genetics & Development 2014, 25:131–137 This review comes from a themed issue on Genome architecture and expression Edited by Victor Corces and David L Levens For a complete overview see the Issue and the Editorial 0959-437X/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.gde.2013.11.009

SMC complexes The structural maintenance of chromosome (SMC) complexes are ring-shaped protein complexes that can link two DNA molecules (Figure 1) [1,2]. These complexes can accommodate two nucleosome-bound DNA molecules within the ring, although other mechanisms have been proposed for the ability of these complexes to link DNA [2–5]. SMC complexes are composed of two SMC subunits that act as long coiled-coil arms, a kleisin subunit that bridges the gap between the arms, and one or two heat repeat-containing subunits [1]. This general subunit composition is conserved from the single bacterial SMC complex through the various complexes found in vertebrates. Mammalian cells possess multiple SMC complexes with varied functions, which include mitotic cohesin, meiotic cohesin, condensin I, condensin II, and the SMC5/SMC6 DNA repair complex [6,7]. Bacteria possess a single SMC complex that functions in chromosome partitioning and proper nucleoid structure [8,9]. Eukaryotic SMC complexes were first shown to play important roles in chromosome maintenance during the cell cycle; cohesin maintains sister chromatid cohesion www.sciencedirect.com

and condensin contributes to the compaction of chromosomes during mitosis [1,2,10,11]. Cohesin and condensin were later found to have roles in gene expression and interphase chromatin organization, which is the focus of this review.

SMC-mediated control of gene expression Early evidence that SMC complexes make functional contributions to gene regulation came from studies of gene expression and dosage compensation in yeast, Drosophila melanogaster and Caenorhabditis elegans [12,13]. In yeast, cohesin was found to be involved in the silencing of heterochromatin [14,15]. Reduction of cohesin levels by as much as 80% caused defects in transcription, but had little effect on normal sister chromatid cohesion and chromosome segregation, suggesting that normal levels of cohesin are especially important for gene control [16,17]. In flies, the cohesin loading protein Nipped-B was found to contribute to gene activation [18] and disruption of cohesin was shown to affect expression of hundreds of genes, leading to developmental deficits [16,19,20]. Condensin mutations were found to alter the position effect variegation of reporter genes in D. melanogaster [21]. Dosage compensation in C. elegans was also found to be controlled by SMC complexes. The C. elegans dosage compensation complex (DCC), which differs from the canonical condensin complex by a single subunit [22,23], was shown to be targeted to the two X chromosomes of hermaphrodites, where it caused a 50% reduction in transcription from genes on each of these chromosomes [24,25]. In vertebrates, cohesin, condensin I and condensin II have been shown to be associated with transcriptionally active enhancers and promoters and appear to contribute to stable enhancer–promoter DNA looping [26,27– 30,31]. Among these SMC complexes, the genome-wide occupancy and function of cohesin is best studied, and these studies have led to the following model for gene activation. During transcription initiation, DNA-binding transcription factors bind to enhancer elements and recruit a variety of cofactors, including the Mediator coactivator, which in turn binds RNA polymerase II at promoter sites, forming an enhancer–promoter DNA loop (Figure 2) [32–35]. The SMC-loading factor NIPBL binds Mediator and loads cohesin at these sites [28,36]. The enhancer–promoter loops mediated by cohesin occur at genes important for cell identity [27,37]. Once loaded at promoters, the cohesin ring is able to translocate along DNA, possibly due to the action of transcribing RNA Polymerase [38,39]. A substantial fraction of cohesin is also associated with CTCF-bound regions of the genome Current Opinion in Genetics & Development 2014, 25:131–137

132 Genome architecture and expression

Figure 1

Cohesin SMC1

Condensin I

SMC3

SMC2

SMC4

Condensin II SMC2

SMC4

RAD21

CAPH

CAPH2

STAG

CAPD2 CAPG

CAPD3 CAPG2

Current Opinion in Genetics & Development

Subunit composition of the mammalian SMC complexes cohesin, condensin I and condensin II.

[28,40], and this may be a consequence of NIPBL-dependent loading of cohesin at promoters followed by translocation to CTCF sites, or NIPBL-independent loading of cohesin at CTCF sites. Some of these cohesin-associated CTCF sites interact with regulatory elements and facilitate gene activation, while others are found at the boundary elements of topological domains, where they function as insulators, thus preventing the spread of an active transcriptional state beyond the boundary [40–45,46,47–53]. Vertebrates have two condensin complexes that associate sequentially with chromosomes during the cell cycle, show distinct patterns of binding to mitotic chromosomes and play different roles in chromosome architecture [54– 57]. Condensin II is present in the nucleus throughout the cell cycle and is required for chromosome condensation during early prophase [55,57]. Condensin I, which is excluded from the nucleus during interphase, is loaded

Figure 2

Transcription Factors

SMC complex Mediator Pol II NIPBL

Current Opinion in Genetics & Development

Model for loading and translocation of SMC complexes during transcription. Transcription factors bind to enhancers and recruit the Mediator coactivator, NIPBL, and RNA Polymerase. NIPBL loads the SMC complexes at these regulatory elements where they contribute to the formation or stability of the enhancer–promoter DNA loop. Transcription elongation may facilitate translocation of SMC complexes to other regions of the chromosome. Current Opinion in Genetics & Development 2014, 25:131–137

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SMCs link gene expression and genome architecture Dowen and Young 133

onto chromosomes during prometaphase, when it is required for complete removal of cohesin from chromosome arms, chromosome shortening and normal metaphase progression [55,57,58]. The condensins are thought to encircle DNA and act as a clamp during condensation, thereby providing structural integrity to segregating chromosomes [1,12,59,60,61]. Low-resolution imaging suggests that condensins I and II occupy discrete domains that cover the length of mitotic chromosomes [55–57]. However, recent high-resolution ChIP-seq studies show that condensins I and II occupy the same regions of the genome with both complexes present at enhancers, promoters, centromeres and telomeres, and absent from heterochromatic regions [26,31]. Loading of the condensin complexes at actively transcribed genes depends, like cohesin, on the function of the SMC-loading factor NIPBL [26,62].

Regulation of SMC complexes at genes Regulation of SMC loading and unloading at the enhancer–promoter interface is almost certainly a highly dynamic process, but is not yet well understood. Contact with the activation domains of transcription factors causes a modification in the structure of the Mediator complex that is thought to enhance NIPBL binding to Mediator, and this may be an underlying mechanism that regulates cohesin loading [63]. The functions of SMC complexes in sister chromatid cohesion can be regulated by phosphorylation, acetylation and sumoylation of their subunits, but it is not yet clear whether these modifications also play roles in gene regulation [64,65]. Cohesin removal is also important for normal gene expression [66]. Removal of SMC complexes from DNA is thought to occur through two different mechanisms, one that operates predominantly in chromosome arms and the other in centromeric DNA [67]. During the cell cycle, most cohesin molecules are removed from chromosome arms in prophase via the action of WAPL [66,68]. In WAPLdepleted cells, cohesin occupancy at transcription starts sites is altered and expression of many genes is changed [66]. Recent studies suggest that WAPL mediates a transient opening of the cohesin ring at the SMC3/kleisin interface [69,70,71]. The second mechanism of cohesin release occurs during anaphase when sister chromatid cohesion is lost and cohesin molecules are released from centromeres via proteolytic cleavage by Separase [72,73].

SMC complexes in control of cell identity Super-enhancers are large clusters of transcriptional enhancers that drive expression of the key genes that control and define cell identity [26,27,74,75]. These domains are associated with genes encoding master transcription factors and other key proteins that play important roles in the biology of these cells. The importance of these domains is emphasized by the observation that www.sciencedirect.com

sequence variation associated with a broad spectrum of diseases is especially enriched in the super-enhancers of disease-relevant cell types [27,76]. Super-enhancers contain unusually high levels of Mediator and SMC complexes; on the basis of ChIP-seq reads, 20–40% of the Mediator, cohesin and condensin II protein associated with enhancers in murine embryonic stem cells is bound to the 230 super-enhancers [26,74]. Furthermore, knockdown of mediator, cohesin and condensin II causes a disproportionate loss of transcription of super-enhancerassociated genes [26,74]. These results indicate that transcriptional control of key cell identity genes is especially dependent on Mediator and SMC complexes.

SMC contributions to chromosome structure Chromosomes are organized into a hierarchy of structures, ranging from DNA loops such as enhancer–promoter loops, to topological domains that appear to average 0.8 Mb, to chromosome compartments and territories [46,77,78– 80]. The formation of enhancer–promoter DNA loops at active genes (Figure 2), as well as other loops involving CTCF, produces one level of chromosome organization that is facilitated by SMC complexes. As might be expected, such DNA loops are unique to cell state and change during differentiation and reprogramming [81,82,83,84,115]. These DNA loops are also thought to be dynamic within individual cells [77]. In contrast, topological domains are shared by the different cell types of an organism, conserved across species, and their boundaries contain insulators [46,85]. The expression of genes within a topological domain is generally correlated [77,86–88]. Since the boundaries of topological domains contain CTCF sites, and cohesin is found associated with such sites, it seems likely that cohesin contributes to the structure of topological domains. However, there are conflicting views on this subject, as one recent study detected few changes in topological domain organization upon loss of cohesin, while another study using a higher resolution analysis in a different cell type observed global changes in domain organization [89,90]. It is not yet clear whether the SMC complexes contribute to chromosome compartments, which consist of multiple topological domains, or chromosome territories, which consist of multiple chromosome compartments [77,91,92]. The condensin complexes are thought to contribute to chromosome compaction, which can be viewed as another level of chromosome organization [93,94,95]. Evidence in D. melanogaster and in mammalian cells suggest that SMC complexes are generally associated with transcriptionally active euchromatin and are present at much lower levels within heterochromatin [26,28,96,97]. This is consistent with evidence that these complexes are loaded on chromosome arms by the transcription initiation apparatus, and suggests that the mechanisms involved in gene repression in heterochromatin do not rely on SMC complexes. Current Opinion in Genetics & Development 2014, 25:131–137

134 Genome architecture and expression

SMC mutations and disease Defects in cohesin and condensin can lead to genome disorganization, cell cycle delay, altered transcription and cell death [11,26,28,55–57,65,93,98–100]. Mutations in cohesin and its regulatory proteins cause a broad spectrum of developmental diseases termed cohesinopathies [101,102]. In Cornelia de Lange Syndrome, for example, patients have mutations in the cohesin subunits SMC1 and SMC3, as well as the SMC-loading factor NIPBL [103–105]. Mutations in the cohesin acetyltransferase ESCO2 can cause the related Roberts Syndrome [106,107]. Mutations in SMC proteins are also found in some cancers. Mutations in the cohesin subunit STAG2 frequently occur in a range of tumor types including urothelial bladder cancer and glioblastoma multiforme, while mutations in SMC3 are associated with acute myeloid leukemia and may contribute to its pathogenesis [108–112]. Mutations in two condensin subunits, SMC2 and SMC4, are found in pyothorax-associated lymphoma [113]. Condensin becomes overexpressed in Wntactivated hyperplastic cells allowing for rapid proliferation [114]. It is likely that these cohesin and condensin defects result in the loss of long-range interactions between regulatory elements and their genes, leading to misregulation of cell type-specific gene expression programs.

Conclusions The loading and unloading of SMC complexes at transcriptional regulatory elements links the control of gene expression to the control of chromosome structure. Proper expression of genes that control cell identity is especially dependent on the functions of SMC complexes, and mutations in the SMC complexes cause diseases associated with a loss of cell identity. Thus, improved understanding of the roles of SMC complexes in gene regulation, chromosome structure and cell identity should advance our understanding of the relationships between these important processes and the mechanisms involved in the cohesinopathies and cancer.

Acknowledgements We thank Brian Abraham, Ashley Lau, Xiong Ji, and Heather Hoke for critical reading of the manuscript. This review was supported by the National Institutes of Health under Ruth L Kirschstein National Research Service Award (CA168263-01A1) from the National Cancer Institute (JMD) and by NIH grant HG002668 (RY).

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Current Opinion in Genetics & Development 2014, 25:131–137

SMC complexes link gene expression and genome architecture.

The structural maintenance of chromosomes (SMC) complexes are associated with transcriptional enhancers, promoters and insulators, where they contribu...
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